HoxC5 and Pbx4 repress hTERT to limit telomerase activity
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE97570 | GEO | 2018/02/13
REPOSITORIES: GEO
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Project description:The catalytic subunit of the human telomerase (hTERT) is activated during tumorigenesis in many cancers including prostate cancer (PCa). Androgens mediate their effect through the androgen receptor (AR), a key factor controlling PCa growth. hTERT expression is known to be regulated by androgens, however contrarily observed to be inhibited or activated. Here, we reveal that androgens repress or activate hTERT expression in a concentration-dependent manner. Low physiological androgen levels activate while supraphysiological androgen levels (SAL) repress hTERT expression. We confirmed SAL-mediated gene repression of hTERT in native human PCa samples derived from patients treated ex vivo as well as in cancer spheroids derived from androgen-dependent and castration resistant PCa (CRPC) cells. Interestingly, based on chromatin immunoprecipitation (ChIP) data both a positive androgen response element (pARE) at -4kb distal and a negative response element (nARE) at the proximal -0.1kb promoter region were identified. Focusing on the nARE it was narrowed down to -121 to -58 bp in the core promoter region. ChIP experiments confirmed an androgen-dependent recruitment of AR and the tumor suppressors inhibitor of growth 1 and 2 (ING1 and ING2), recently identified as AR co-repressors. Mechanistically, the knockdown of either ING1 or ING2 reduced androgen-mediated repression of hTERT indicating that ING1 and ING2 mediate AR-regulated transrepression on the hTERT expression. Thus, our data suggest a dual, biphasic function of AR to control hTERT expression by transactivation and transrepression. The inhibition of hTERT by androgens by a nARE located in the proximal promoter region is mediated at least in part by the AR co-repressors ING1 and ING2.
2022-03-04 | GSE155528 | GEO
Project description:To investigate the mechanism of telomerase regulation in BCR-ABL positive cells due to its clinical value, we studied the catalytic component of telomerase, TERT. Our results suggest that BCR-ABL plays an important role in regulating hTERT in K562 (BCR-ABL positive human leukemia) cells. When Gleevec inhibited the tyrosine kinase activity of BCR-ABL, phosphorylation of hTERT was downregulated, therefore suggesting a positive correlation between BCR-ABL and hTERT. Gleevec treatment inhibited hTERT at the mRNA level and significantly reduced telomerase activity (TA) in K562 cells, but not in HL60 or Jurkat cells. TRAP assay also revealed that Gleevec treatment significantly reduced TA specifically in K562 cells. Furthermore, translocation of hTERT from nucleoli to nucleoplasm was observed in K562 cells induced by Gleevec. Although Gleevec down-regulated hTERT mRNA level, the protein level of hTERT remained unchanged. Therefore, Gleevec-induced-TA decrease is not due to the alteration in telomerase subunits expression. It could be presumably due to posttranslational modification of hTERT, possibly through multiple signaling pathways. We have found that Gleevec reduced the tyrosine phosphorylation of hTERT by BCR-ABL, which is associated with the nucleoplasm localization of hTERT from nucleoli sequesters. These findings reveal unknown functions and regulations of telomerase by BCR-ABL.
2011-12-15 | GSE26821 | GEO
Project description:Although high-risk human papillomavirus (HPV) infection plays a major role in the development of cervical cancer, additive oncogenic events are involved as well. One key event involves increased activity of telomerase resulting from a deregulated expression of its catalytic subunit hTERT. Our previous microcell-mediated chromosome transfer studies revealed that introduction of human chromosome 6 in the HPV16 immortalized keratinocyte cell line FK16A and in the HPV16 containing cervical cancer cell line SiHa induced growth arrest, resulting from a repression of hTERT mRNA expression and telomerase activity. Here, this model was used to analyze expression profiles associated with hTERT deregulation in HPV transformed cells. Microarray expression analysis of 12 FK16A/chromosome 6 hybrids, four of which were negative for endogenous hTERT and 8 of which were positive for endogenous hTERT, resulted in the identification of 164 differentially expressed genes. Differential expression of a selection of 5 genes was verified by real-time RT-PCR. Of these 164 genes, 32 were also differentially expressed in other HPV transformed cells with deregulated hTERT. For 2 of these genes, encoding AQP3 and MGP, altered expression in hTERT positive cervical carcinomas was confirmed by real-time RT-PCR and immunohistochemistry, respectively. In summary we identified 32 candidate biomarkers for deregulated hTERT mRNA expression which may enable the identification of cervical premalignant lesions that are at highest risk to progress to invasive cancer. Keywords: microarray expression analysis, hTERT, cervical cancer 12 previously established cell hybrids, all carrying the same genetic background were subjected to microarray expression analysis. These hybrids were generated by the introduction of chromosome 6 in the HPV16 immortalized cell line FK16A, which resulted in a suppression of hTERT expression and telomerase activity. 8 hybrids were endogenous hTERT positive and 8 hybrids were hTERT negative. Additionally primary keratinocytes (hTERT negative), parental cell line FK16A and cervical cancer cell line SiHa (both hTERT positive) were hybridized.
2010-06-25 | E-GEOD-8288 | biostudies-arrayexpress
Project description:Telomere length control is critical for cellular lifespan and tumor suppression. Telomerase is activated in the inner cell mass of the developing blastocyst to reset telomere reserves and its subsequent silencing in differentiated cells leads to gradual telomere shortening. Here, we report that transcriptional control through cis-regulatory elements minimally impact telomerase regulation as a function of pluripotency. Instead, developmental control of telomerase is largely driven by an alternative splicing event, centered around hTERT exon-2. Skipping of exon-2 triggers hTERT mRNA decay in differentiated cells. Conversely, its retention in pluripotent cells promotes telomerase accumulation. Our study also identifies SON as a regulator of exon-2 alternative splicing and we report a patient with insufficient telomerase and short telomeres and harboring a SON mutation. In summary, our study highlights a critical role for hTERT alternative splicing in the developmental regulation of telomerase and implicates defective splicing in telomere biology disorders.
2021-03-04 | GSE168193 | GEO
Project description:Telomerase controls cell immortality and is a promising cancer target. Understanding transcriptional regulation of the catalytic subunit hTERT is critical to realise effective telomerase therapeutics. GSK3 inhibition suppresses hTERT expression.
2009-08-03 | GSE14532 | GEO
Project description:To investigate the mechanism of telomerase regulation in BCR-ABL positive cells due to its clinical value, we studied the catalytic component of telomerase, TERT. Our results suggest that BCR-ABL plays an important role in regulating hTERT in K562 (BCR-ABL positive human leukemia) cells. When Gleevec inhibited the tyrosine kinase activity of BCR-ABL, phosphorylation of hTERT was downregulated, therefore suggesting a positive correlation between BCR-ABL and hTERT. Gleevec treatment inhibited hTERT at the mRNA level and significantly reduced telomerase activity (TA) in K562 cells, but not in HL60 or Jurkat cells. TRAP assay also revealed that Gleevec treatment significantly reduced TA specifically in K562 cells. Furthermore, translocation of hTERT from nucleoli to nucleoplasm was observed in K562 cells induced by Gleevec. Although Gleevec down-regulated hTERT mRNA level, the protein level of hTERT remained unchanged. Therefore, Gleevec-induced-TA decrease is not due to the alteration in telomerase subunits expression. It could be presumably due to posttranslational modification of hTERT, possibly through multiple signaling pathways. We have found that Gleevec reduced the tyrosine phosphorylation of hTERT by BCR-ABL, which is associated with the nucleoplasm localization of hTERT from nucleoli sequesters. These findings reveal unknown functions and regulations of telomerase by BCR-ABL. Using cRNA microarray, gene expression of Gleevec-treated and non-treated K562 (BCR-ABL positive) cells were compared against Gleevec-treated and non-treated HL60 (BCR-ABL deficient) cells.
2011-12-15 | E-GEOD-26821 | biostudies-arrayexpress
Project description:Although high-risk human papillomavirus (HPV) infection plays a major role in the development of cervical cancer, additive oncogenic events are involved as well. One key event involves increased activity of telomerase resulting from a deregulated expression of its catalytic subunit hTERT. Our previous microcell-mediated chromosome transfer studies revealed that introduction of human chromosome 6 in the HPV16 immortalized keratinocyte cell line FK16A and in the HPV16 containing cervical cancer cell line SiHa induced growth arrest, resulting from a repression of hTERT mRNA expression and telomerase activity. Here, this model was used to analyze expression profiles associated with hTERT deregulation in HPV transformed cells. Microarray expression analysis of 12 FK16A/chromosome 6 hybrids, four of which were negative for endogenous hTERT and 8 of which were positive for endogenous hTERT, resulted in the identification of 164 differentially expressed genes. Differential expression of a selection of 5 genes was verified by real-time RT-PCR. Of these 164 genes, 32 were also differentially expressed in other HPV transformed cells with deregulated hTERT. For 2 of these genes, encoding AQP3 and MGP, altered expression in hTERT positive cervical carcinomas was confirmed by real-time RT-PCR and immunohistochemistry, respectively. In summary we identified 32 candidate biomarkers for deregulated hTERT mRNA expression which may enable the identification of cervical premalignant lesions that are at highest risk to progress to invasive cancer. Keywords: microarray expression analysis, hTERT, cervical cancer
2008-06-25 | GSE8288 | GEO
Project description:The complexity and heterogeneity of cancer cells are under-represented by the current experimental models which revolve around primary tumor cells, cancer cell lines, and rodent models. We used the transformed cell model in our studies. IMR90 and BJ fibroblast cells were transformed by three oncogenic genetic factors, SV40 Large-T antigen, H-Ras and human telomerase (hTERT). These transformed cells can grow under anchorage independent conditions, are self-sufficient in growth signals, have decreased sensitivity to apoptosis, and showed recurrent chromosomal abnormalities. Further characterization of transformed cells through cell cycle profiling and mass spectrometry analysis also revealed an increased fraction in the G2/M phase, and an up-regulation of Ku70. Furthermore, transformed cells exhibited increased telomerase activity that was not accountable by hTERT overexpression alone. Microarray results revealed that hTERT overexpression promoted cell migration and the initiation of DNA damage responses; two cellular processes that are important in cancer progression. Collectively, these data imply that IMR90 transformed cell model is an invaluable tool for cancer studies. Our results in the systematic study of this model helped us identify possible early events in cancer transformation and reveal the extra-telomeric effects of telomerase in cell migration and DNA damage initiation. IMR90 and BJ fibroblast cells were transformed by three oncogenic genetic factors, SV40 Large-T antigen, H-Ras and human telomerase (hTERT). Through microarray analysis, gene expression of transformed cells were compared against control cells.
2010-12-31 | E-GEOD-24097 | biostudies-arrayexpress
Project description:Introduction: Pleural mesothelioma (PM) is known as one of the most aggressive malignancies among all cancers, despite of usually absent tumor-driver mutations in oncogenes. It develops in a unique inflammatory tumor microenvironment (TME), which has been postulated as major contributor of PM’s highly aggressive nature. Mesothelioma-associated fibroblasts (Meso-CAFs), a main component of the TME have recently been shown to substantially stimulate several aspects of PM aggressiveness and promote the malignant transformation of pleural mesothelial cells. However, respective cell models for TME research in PM are still very limited. The most commonly used pleural mesothelial cell line Met5A has been established decades ago and patient-derived Meso-CAFs have just recently been characterized for the first time. The aim of the current study was to generate and characterize pleural mesothelial and Meso-CAF cell models with an extended life span that closely resemble the primary cells isolated from human tissue. Methods: Pleural mesothelial cells and Meso-CAFs were isolated from human tissue of pneumothorax and PM patients, respectively. Retroviral transduction was used to induce stable expression of human telomerase reverse transcriptase (hTERT) and enhanced green fluorescent protein (EGFP) in the primary cells. The established cell models were evaluated by measuring their doubling times, gene expression and protein activity levels of hTERT, as well as the absolute lengths of telomeres. The transduced cells were compared to their primary counterparts on the protein level using proteome analysis and the impact of their conditioned media (CM) on tumor cell growth was investigated by videomicroscopy. Results: All transduced derivatives exhibit elevated hTERT gene expression and protein activity, increased hTERT protein amounts in the nucleus, and moderately higher absolute telomere lengths compared to their parental primary cells. The transduction with hTERT did not elicit marked changes in the morphology of the cells, as well as in their proteomes and secretomes. The CM of primary and hTERT-transduced Meso-CAFs comparably stimulated PM cell growth, while medium conditioned by normal pleural mesothelial cells including their hTERT-transduced derivatives was not able to induce a growth stimulating effect. Conclusion: The hTERT-transduced cells closely resemble their primary counterparts, while retaining telomerase activity, thus preventing replicative senescence. The new cell models provide valuable tools for the investigation of cellular interactions cellular interactions within the TME of PM and thus may help to identify novel biomarkers for early diagnosis and to develop new therapeutic strategies.
2023-10-24 | PXD043511 | Pride
Project description:Replicative senescence forms a major barrier to tumor progression. Cancer cells bypass this by using one of the two known telomere maintenance mechanisms: telomerase or the recombination-based alternative lengthening of telomeres (ALT) mechanism. The molecular details of ALT are currently poorly understood. We have previously shown that telomerase is actively repressed through complex networks of kinase, gene expression, and chromatin regulation. In this study, we aimed to gain further understanding of the role of kinases in the regulation of telomerase expression in ALT cells. Using a whole human kinome siRNA screen, we highlighted 106 kinases whose expression is linked to hTERT promoter activity. Network modeling of transcriptional regulation implicated c-Myc as a key regulator of the 106 kinase hits. Given our previous observations of lower c-Myc activity in ALT cells, we further explored its potential to regulate telomerase expression in ALT. We found increased c-Myc binding at the hTERT promoter in telomerase-positive compared with ALT cells, although no expression differences in c-Myc, Mad, or Max were observed between ALT and telomerase-positive cells that could explain decreased c-Myc activity in ALT. Instead, we found increased expression of the c-Myc competitive inhibitor TCEAL7 in ALT cells and tumors and that alteration of TCEAL7 expression levels in ALT and telomerase-positive cells affects hTERT expression. Lower c-Myc activity in ALT may therefore be obtained through TCEAL7 regulation. Thus, TCEAL7 may present an interesting novel target for cancer therapy, which warrants further investigation.
2010-05-04 | GSE17118 | GEO